Project Summary/Abstract: This proposal describes a four-year training project, which will prepare the applicant to achieve the goal of becoming an independent investigator in diabetes and neurobiology research. The research proposed here aims to better understand insulin and IGF-1 signaling in the brain, which will have potential implications for public health. The applicant also proposes a detailed training plan, which includes further training in specialized techniques and attending scientific and career development seminars and courses. The applicant has assembled an outstanding Boston-based mentoring team to support the research as well as career development throughout the training period. The applicant will be co-mentored by Dr. C. Ronald Kahn, a renowned expert in insulin signaling and diabetes research, at Joslin Diabetes Center, Harvard Medical School, and Dr. Philip Haydon, a pioneer and expert in astrocyte biology and gliotransmission, at Tufts University College of Medicine. In addition, the applicant will receive technical and intellectual support from scientific advisors Drs. Emmanuel Pothos and Bradford Lowell. Insulin is known to act in the brain to suppress appetite and to improve cognition and depression symptoms. Patients with diabetes have a greater risk to develop neurological disorders, including Alzheimer's disease and major depression. Loss of insulin receptors in the brain leads to overfeeding, insulin resistance and more depressive-like behaviors in mice. All of these indicate that insulin is a key regulator to maintain normal neurophysiology. However, the mechanism by which insulin signaling in the brain controls neurobehaviors is still not fully understood. My preliminary studies show that mice with astrocyte-specific insulin receptor deletion exhibit increased depressive-like behavior, which indicates that insulin signaling originated from astrocytes is important for regulation of neuronal activity and behaviors. The overall goal of this project is to characterize the relative roles of insulin receptor (IR) and IGF-1 receptor (IGF1R) in astrocytes for neural functions and behaviors. The central hypothesis is that IR, and possibly IGF1R, signaling is important for normal metabolism and function of astrocytes, and that loss of these actions will lead to altered neurotransmitter homeostasis, which secondarily modulates dopaminergic neuronal activity, thus altering behaviors. Aim 1 will define the cell autonomous roles of IR and IGF1R in astrocytes on the regulation of intracellular signaling, cellular metabolism, neurotransmitter release, which could contribute to neuronal regulation. Aim 2 will examine the roles of IR and IGF1R in astrocytes on dopaminergic neural circuitry and mood regulation in normal and diabetic conditions. These studies will expand our knowledge of IR and IGF1R signaling in the brain under normal physiological condition and in the context of diabetes and insulin resistance, and could provide new avenue for prevention and therapy of diabetes and many other disorders.